This invention relates to novel semi-synthetic macrolides and ketolides having antibacterial activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, this invention concerns to C12 modified erythromycin macrolides and ketolide derivatives, compositions containing these compounds, methods of producing the compounds and methods of treating bacterial infections.
Erythromycins A through D, represented by formula (I):
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity. For example, the compound 6-OMe erythromycin A, or clarithromycin, has found widespread use. However, even this compound is beginning to lose its effectiveness and other erythromycin derivatives having improved activity are needed. Other 6-O-substituted erythromycin compounds have also been proposed for this purpose. For example, PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives. U.S. Pat. No. 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A derivatives in which the substituents are selected from alkyl, xe2x80x94CONH2, xe2x80x94CONHC(O)alkyl and xe2x80x94CONHSO2 alkyl. PCT application WO 97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose erythromycin derivatives. European Patent Application 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.
More recently, a class of 3-O ketolide erythromycin derivatives have been disclosed in U.S. Pat. Nos. 6,147,197 and 5,635,485. Representative lead compounds in this class include, for example ABT-773 disclosed in U.S. Pat. No. 6,147,197 and telithromycin disclosed in U.S. Pat. No. 5,635,485. The structures of these compounds are as follows: 
Other modifications that have shown promise include modifications at C2, including, for example, those shown in U.S. Pat. No. 6,124,269 and International Application Publication No. WO 00/69875, the disclosures of which are incorporated herein by reference.
Despite much activity in designing 14-membered macrolide derivatives, few examples of modifications at C12 exist, especially with regards to the C12-C21 bond. U.S. Pat. No. 4,857,641 (Hauske) discloses that when the C9-C11 erythromycin positions are protected as cyclic thiocarbonates, the C12 OH can be selectively activated and eliminated over the C6 OH to give an exocyclic double bond, and the thiocarbonate protecting group can then be removed reductively with NaBH. Stereoselective dihydroxylation is disclosed as the sole olefin modification. U.S. Pat. No. 5,217,960 (Lartey), discloses that the above C12 exocyclic alkene formation of Hauske can also be effected with a protected amino group at C9 and a formate ester at C11. However, elimination at C6 did occur, suggesting that the C9 amino substituent does not provide as great a steric impediment to C6 OH activation as does the Hauske C9 thiocarbonate. The desired C12 olefin could be separated and isolated, and is disclosed as participating in stereoselective epoxidation, dihydroxylation, and hydroboration reactions, wherein all reagents attack the same face of the olefin (top face if the macrolide is drawn as shown above). Of these products, only the epoxide is disclosed as being derivatized by ring opening with alkyl amines. (Ring opening with other nucleophiles is suggested, but only generally, and no specific examples are given). It should be noted that the C12 modified compounds of Hauske and Lartey exhibit minimal antibacterial activity. 
Efficient strategies for synthetic modifications involving the C12-C21 bond rely, in part, on the ability to selectively differentiate between the aglycon alcohols of erythromycin A. The differentiation appears to be dependent upon the identity of the C9 substituent, although the order and degree of selectivity can be difficult to predict. For example, the reactivity of the aglycon alcohols generally decrease when comparing C11 to C6 to C12. However as seen in the Hauske and Lartey examples above, the C12 OH can become more reactive than the C6 OH if the C9 ketone is modified in a particular manner. Alternatively when the C9 ketone is functionalized as various oximes (see U.S. Pat. No. 6,147,195), the C6 OH can be selectively alkylated over both C12 and C11. Finally, it has been shown that when erythromycin A is treated with NaBH4 to form a bis-erythromycin A borate ester followed by alkylation with MeI, selective methylation occurs at C12 over both C11 and C6 (JOC, 1999, p. 2107).
The present invention provides novel 14 membered macrolide and ketolide antibiotics containing C12 modifications, useful common intermediates for introducing C12 modifications, methods for their synthesis, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
In one embodiment, the present invention provides compounds of the following formula (II): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein
A. V is xe2x80x94OCORx, carbonyl, or a cladinose moiety of the formula: 
xe2x80x83wherein Rx is H, alkyl, xe2x80x94O-alkyl, xe2x80x94N(H)-alkyl, or xe2x80x94N(alkyl)2;
B. either Y and Z taken together define a group X, wherein X is selected from the group consisting of
(1) xe2x95x90O,
(2) xe2x95x90Nxe2x80x94OH,
(3) xe2x95x90Nxe2x80x94Oxe2x80x94R1 where R1 is selected from the group consisting of
(a) C1-C12-alkyl,
(b) C1-C12-alkyl substituted with alkoxy,
(c) C1-C12-alkyl substituted with aryl,
(d) C1-C12-alkyl substituted with substituted aryl,
(e) C1-C12-alkyl substituted with heteroaryl,
(f) C1-C12-alkyl substituted with substituted heteroaryl,
(g) C3-C12-cycloalkyl, and
(h) xe2x80x94Sixe2x80x94(R2)(R3)(R4) wherein R2, R3, R4 are each independently selected from C1-C12-alkyl and aryl; and
(4) xe2x95x90Nxe2x80x94Oxe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94R1 wherein R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-C12-alkyl,
(c) C1-C12-alkyl substituted with aryl,
(d) C1-C12-alkyl substituted with substituted aryl,
(e) C1-C12-alkyl substituted with heteroaryl, and
(f) C1-C12-alkyl substituted with substituted heteroaryl;
or R5 and R6 taken together with the atoms to which they are attached form a C3-C12-cycloalkyl ring; or
Y and Z are xe2x95x90Nxe2x80x94 when taken together with T to form a moiety of the structure: 
xe2x80x83or
one of Y and Z is hydrogen and the other is selected from a group consisting of
(1) hydroxy,
(2) protected hydroxy, and
(3) NR7R8 wherein R7 and R8 are independently selected from hydrogen and alkyl, subsituted alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NH, xe2x80x94N(C1-C6-alkyl)-, xe2x80x94N(aryl)-, xe2x80x94N(aryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-aryl-C1-C6-alkyl-)-, xe2x80x94N(heteroaryl)-, xe2x80x94N(heteroaryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-heteroaryl-C1-C6-alkyl-)-, and xe2x80x94Sxe2x80x94 or S(O)nxe2x80x94 wherein n is 1 or 2;
C. T is selected from the group consisting of xe2x80x94Oxe2x80x94Rg, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, N(Wxe2x80x94Rf)xe2x80x94, and xe2x80x94CH(Wxe2x80x94Rf)xe2x80x94, wherein
(1) W is absent or is selected from the group consisting of xe2x80x94Oxe2x80x94, NHxe2x80x94COxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94 and xe2x80x94CH2xe2x80x94; and
(2) Rf is selected from the group consisting of
(a) hydrogen,
(b) alkyl, alkenyl or alkynyl,
(c) alkyl, alkenyl or alkynyl substituted with one or more substituents selected from the group consisting of
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) substituted heteroaryl,
(v) hydroxy,
(vi) C1-C6-alkoxy,
(vii) xe2x80x94NR7R8 wherein R7 and R8 are as defined previously, and
(viii) xe2x80x94Mxe2x80x94R9, wherein M is selected from the group consisting of:
xe2x80x83(a) xe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x83(b) xe2x80x94NHxe2x80x94C(O)xe2x80x94,
xe2x80x83(c) xe2x80x94NHxe2x80x94,
xe2x80x83(d) xe2x80x94Nxe2x95x90,
xe2x80x83(e) xe2x80x94N(CH3)xe2x80x94,
xe2x80x83(f) xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94,
xe2x80x83(g) xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x83(h) xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94xe2x80x94,
xe2x80x83(i) xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
xe2x80x83(j) xe2x80x94Oxe2x80x94,
xe2x80x83(k) xe2x80x94S(O)nxe2x80x94, wherein n is 0, 1 or 2,
xe2x80x83(l) xe2x80x94C(O)xe2x80x94Oxe2x80x94,
xe2x80x83(m) xe2x80x94Oxe2x80x94C(O)xe2x80x94,
xe2x80x83(n) xe2x80x94C(O)xe2x80x94; and
and R9 is selected from the group consisting of:
(a) alkyl optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted aryl,
(cc) heteroaryl, and
(dd) substituted heteroaryl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl, and
(f) heterocycloalkyl,
D. R is selected from the group consisting of
(1) hydrogen;
(2) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) xe2x80x94CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl,
(d) xe2x80x94S(O)nR10xe2x80x94, wherein n is 0, 1 or 2 and R10 is as previously defined,
(e) xe2x80x94NHxe2x80x94C(O) R10, wherein R10 is as previously defined,
(f) xe2x80x94NHxe2x80x94C(O)N R11 R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl;
(3) alkyl;
(4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) C1-C3-alkoxy,
(d) C1-C3-alkoxy-C1-C3-alkoxy,
(e) oxo,
(f) Oxe2x80x94SO2-(substituted C1-C6-alkyl),
(g) xe2x80x94N3,
(h) xe2x80x94CHO,
(i) xe2x80x94NR13R14 wherein R13 and R14 are selected from the group consisting of
(i) hydrogen,
(ii) C1-C12-alkyl,
(iii) substituted C1-C12-alkyl,
(iv) C2-C12-alkenyl,
(v) substituted C2-C12-alkenyl,
(vi) C2-C12-alkynyl,
(vii) substituted C2-C12-alkynyl,
(viii) aryl,
(ix) C3-C8-cycloalkyl,
(x) substituted C3-C8-cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C1-C12-alkyl substituted with aryl,
(xv) C1-C12-alkyl substituted with substituted aryl,
(xvi) C1-C12-alkyl substituted with heterocycloaryl,
(xvii) C1-C12-alkyl substituted with substituted heterocycloaryl,
(xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
(xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C1-C12-alkyl substituted with heteroaryl, and
(xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
or R13 and R14 are taken together with the atom to which they are attached form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C1-C3-alkoxy,
(iv) C1-C3-alkoxy-C1-C3-alkoxy,
(v) oxo,
(vi) C1-C3-alkyl,
(vii) halo-C1-C3-alkyl, and
(viii) C1-C3-alkoxy-C1-C3-alkyl;
(j) xe2x80x94CO2R10 wherein R10 is as previously defined,
(k) xe2x80x94C(O)R11R12 wherein R11 and R12 are as previously defined,
(l) xe2x95x90Nxe2x80x94Oxe2x80x94R10 wherein R10 is as previously defined,
(m) xe2x80x94CN,
(n) xe2x80x94Oxe2x80x94S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously defined,
(o) aryl,
(p) substituted aryl,
(q) heteroaryl,
(r) substituted heteroaryl,
(s) C3-C8-cycloalkyl,
(t) substituted C3-C8-cycloalkyl,
(u) C1-C12-alkyl substituted with heteroaryl,
(v) heterocycloalkyl,
(w) substituted heterocycloalkyl,
(x) xe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined,
(y) xe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(z) xe2x95x90Nxe2x80x94NRC13R14 wherein R13 and R14 are as previously defined,
(aa) xe2x95x90Nxe2x80x94R9 wherein R9 is as previously defined,
(bb) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined, and
(cc) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined;
(5) C3-alkenyl substituted with a moiety selected from the group consisting of
(a) halogen,
(b) xe2x80x94CHO,
(c) xe2x80x94CO2R10 wherein R10 is as previously defined,
(d) xe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(e) xe2x80x94C(O)R9 wherein R9 is as previously defined,
(f) xe2x80x94CN,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
(j) substituted heteroaryl,
(k) C3-C8-cycloalkyl, and
(l) C1-C12-alkyl substituted with heteroaryl;
(6) C4-C10-alkenyl;
(7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) C1-C3-alkoxy,
(c) oxo,
(d) xe2x80x94CHO,
(e) xe2x80x94CO2R10 wherein R10 is as previously defined,
(f) xe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(g) NR13R14 wherein R13 and R14 are as previously defined,
(h) xe2x95x90Nxe2x80x94Oxe2x80x94R10 wherein R10 is as previously defined,
(i) xe2x80x94CN,
(j) xe2x80x94Oxe2x80x94S(O), R10 wherein n is 0, 1 or 2 and R10 is as previously defined,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) C3-C8-cycloalkyl,
(p) C1-C12-alkyl substituted with substituted heteroaryl,
(q) xe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined,
(r) xe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(s) xe2x95x90Nxe2x80x94NR13R14 wherein R13 and R14 are as previously defined,
(t) xe2x95x90Nxe2x80x94R9 wherein R9 is as previously defined,
(u) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined, and
(v) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined;
(8) C3-C10-alkynyl;
(9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
(a) trialkylsilyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl, and
(e) substituted heteroaryl; and
(10) C(O)NR7R8 where R7 and R8 are previously defined;
E. Ra is selected from a group consisting of
(1) hydrogen;
(2) C1 alkyl further substituted with a one or more substituents selected from a group consisting of
(a) hydroxyl,
(b) halogen,
(c) thiol, which can be further subsituted with and alkyl or subsituted alkyl group
(d) C1-C12-alkyl which can be further substituted by halogen, hydroxyl alkoxy, or amino,
(e) C1-C3-alkoxy,
(f) C1-C3-thioalkoxy,
(g) amino,
(h) alkylamino,
(i) dialkylamino,
(j) nitrile,
(k) nitro,
(l) amido,
(m) carboxylic acid,
(n) ester,
(o) azido,
(p) xe2x95x90Nxe2x80x94Oxe2x80x94R10, wherein R10 is as previously defined,
(q) xe2x95x90Nxe2x80x94R9, wherein R9 is as previously defined,
(r) xe2x95x90Nxe2x80x94NR13R4, wherein R13 and R14 are as previously defined,
(s) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)R10, wherein R10 is as previously defined, and
(t) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)NR11R12, wherein R11 and R12 are as previously defined;
(3) C2-C4-alkenyl, which can be further substituted With C1-C12-alkyl and one or more halo groups;
(4) xe2x80x94C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
(5) aryl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
(6) CHO;
(7) xe2x80x94CO2H;
(3) xe2x80x94CN;
(9) xe2x80x94CO2R10, wherein R10 is as previously defined;
(10) xe2x80x94C(O)NR11R11R12, wherein R11 and R12 are as previously defined;
(11) xe2x80x94C(O)R9 wherein R9 is as previously defined; and
(12) thioester;
with the proviso that in formula II, when Z is amino or substituted amino, then Ra can not be xe2x80x94CH2OH, xe2x80x94NR4R6, or xe2x80x94(CH2)n NR4R6, wherein R4 and R6 are selected from the group consisting of hydrogen, loweralkyl and aralkyl;
F. Rb is hydrogen, halogen or C1-C12-alkyl which can be further substituted by one or more halo groups, or Rb can be taken together with V to form a double bond;
G. Rc is hydrogen or a hydroxy protecting group;
H. Rd is selected from the group consisting of
(1) C1-C12-alkyl,
(2) C1-C12-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy, and
(c) C1-C3-alkoxy,
(3) C3-C7-cycloalkyl,
(4) C2-C4-alkenyl, and
(5) C2-C4-alkynyl;
I. Re is hydroxyl, amino, or alkylamino; or Re and Ra may be taken together to form an epoxide, a carbonyl, an olefin, or a subsituted olefin; or Re and Ra when taken together with the atom to which they are attached form a Spiro ring consisting of C3-C7-carbocyclic, carbonate or carbamate wherein the nitrogen atom can be unsubstituted or substituted with an alkyl group; or Re and T when taken together with the carbon atoms to which they are attached form a ring of the structure: 
xe2x80x83wherein L is methylene or carbonyl and P is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NR1xe2x80x94 wherein R1 is as previously defined; provided that when L is methylene, T is xe2x80x94Oxe2x80x94 and P is xe2x80x94Oxe2x80x94;
J. Rg is hydrogen, R where R is as previously defined; or Rg may be taken together with Y, separated by a linker of the formula xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94, to form a cyclic moiety;
K. Rh is selected from the group consisting of
(1) hydrogen,
(2) xe2x80x94ORj, where Rj is hydrogen or a hydroxy protecting group,
(3) halogen,
(4) OC(O)NHRi wherein Ri is selected from a group consisting of
(a) C1-C4 alkyl,
(b) C1-C4 aminoalkyl where the amino group is substituted with one or two groups selected from
(i) C1-C4 alkyl,
(ii) C1-C4 alkyl substituted with halogen,
(iii) C1-C4 alkyl substituted with alkoxy,
(iv) C1-C4 alkyl substituted with hydroxyl,
(v) C1-C4 alkyl substituted with aryl,
(vi) C1-C4 alkyl substituted with substituted aryl,
(vii) C1-C4 alkyl substituted with heteroaryl,
(viii) C1-C4 alkyl substituted with substituted heteroaryl,
(ix) C3-C6 cycloalkyl; and
L. A, B, D, and E are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of:
(a) aryl,
(b) substituted aryl,
(c) heteroaryl,
(d) substituted heteroaryl,
(e) heterocycloalkyl,
(f) hydroxy,
(g) C1-C6-alkoxy,
(h) halogen selected from the group consisting of Br, Cl, F or I, and
(i) NR7R8 where R7 and R8 are as previously defined;
(3) C3-C7-cycloalkyl;
(4) aryl;
(5) substituted aryl;
(6) heteroaryl;
(7) substituted heteroaryl;
(8) heterocycloalkyl; and
(9) a group selected from option (2) above further substituted with xe2x80x94Mxe2x80x94R9, wherein M and R9 are as previously defined; or
any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(C1-C6-alkyl-)-, xe2x80x94N(aryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-aryl-C1-C6-alkyl-)-, xe2x80x94N(heteroaryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-heteroaryl-C1-C6-alkyl-)-, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)nxe2x80x94, wherein n is 1 or 2, xe2x80x94C(O)xe2x80x94NH, xe2x80x94C(O)xe2x80x94NR12, wherein R12 is as previously defined, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94NR12xe2x80x94C(O)xe2x80x94, wherein R12 is as previously defined, and xe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94; with the provision that at least two of A, B, D, and E are hydrogen.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (III): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rc, Rd, Re, Rg and Rh have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (IV): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rb, Rc, Rd, Re, and Rg have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (V): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, Y, Z, R, Ra, Re, Rd, and Rh have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (VI): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rb, Rc, and Rd have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (VII): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, D, E, R, Ra, Rb, Rc, and Rd have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (VIII): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rc, and Rd have the meanings defined above.
The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.
The invention further relates to methods of treating bacterial infections in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention as defined above.
In a further aspect of the present invention are provided processes for the preparation of macrolide derivatives of Formulas (II), (III), (IV), (V), (VI), (VII) and (VIII), above.
In one embodiment, the present invention provides compounds of the following formula (II): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein
A. V is xe2x80x94OCORx, carbonyl, or a cladinose moiety of the formula: 
xe2x80x83wherein Rx is H, alkyl, xe2x80x94O-alkyl, xe2x80x94N(H)-alkyl, or xe2x80x94N(alkyl)2;
B. either Y and Z taken together define a group X, wherein X is selected from the group consisting of
(1) xe2x95x90O,
(2) xe2x95x90Nxe2x80x94OH,
(3) xe2x95x90Nxe2x80x94Oxe2x80x94R1 where R1 is selected from the group consisting of
(a) C1-C12-alkyl,
(b) C1-C12-alkyl substituted with alkoxy,
(c) C1-C12-alkyl substituted with aryl,
(d) C1-C12-alkyl substituted with substituted aryl,
(e) C1-C12-alkyl substituted with heteroaryl,
(f) C1-C12-alkyl substituted with substituted heteroaryl,
(g) C3-C12-cycloalkyl, and
(h) xe2x80x94Sixe2x80x94(R2)(R3)(R4) wherein R2, R3, R4 are each independently selected from C1-C12-alkyl and aryl; and
(4) xe2x95x90Nxe2x80x94Oxe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94R1 wherein R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of
(a) hydrogen,
(b) C1-C12-alkyl,
(c) C1-C12-alkyl substituted with aryl,
(d) C1-C12-alkyl substituted with substituted aryl,
(e) C1-C12-alkyl substituted with heteroaryl, and
(f) C1-C12-alkyl substituted with substituted heteroaryl;
or R5 and R6 taken together with the atoms to which they are attached form a C3-C12-cycloalkyl ring; or
Y and Z are xe2x95x90Nxe2x80x94 when taken together with T to form a moiety of the structure: 
xe2x80x83or
one of Y and Z is hydrogen and the other is selected from a group consisting of
(1) hydroxy,
(2) protected hydroxy, and
(3) NR7R8 wherein R7 and R8 are independently selected from hydrogen and alkyl, subsituted alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NH, xe2x80x94N(C1-C6-alkyl)-, xe2x80x94N(aryl)-, xe2x80x94N(aryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-aryl-C1-C6-alkyl-)-, xe2x80x94N(heteroaryl)-, xe2x80x94N(heteroaryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-heteroaryl-C1-C6-alkyl-)-, and xe2x80x94Sxe2x80x94 or S(O)nxe2x80x94 wherein n is 1 or 2;
C. T is selected from the group consisting of xe2x80x94Oxe2x80x94Rg, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, N(Wxe2x80x94Rf)xe2x80x94, and xe2x80x94CH(Wxe2x80x94Rf)xe2x80x94, wherein
(1) W is absent or is selected from the group consisting of xe2x80x94Oxe2x80x94, NHxe2x80x94COxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94 and xe2x80x94CH2xe2x80x94; and
(2) Rf is selected from the group consisting of
(a) hydrogen,
(b) alkyl, alkenyl or alkynyl,
(c) alkyl, alkenyl or alkynyl substituted with one or more substituents selected from the group consisting of
(i) aryl,
(ii) substituted aryl,
(iii) heteroaryl,
(iv) substituted heteroaryl,
(v) hydroxy,
(vi) C1-C6-alkoxy,
(vii) xe2x80x94NR7R8 wherein R7 and R8 are as defined previously, and
(viii) xe2x80x94Mxe2x80x94R9, wherein M is selected from the group consisting of:
xe2x80x83(a) xe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x83(b) xe2x80x94NHxe2x80x94C(O)xe2x80x94,
xe2x80x83(c) xe2x80x94NHxe2x80x94,
xe2x80x83(d) xe2x80x94Nxe2x95x90,
xe2x80x83(e) xe2x80x94N(CH3)xe2x80x94,
xe2x80x83(f) xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94,
xe2x80x83(g) xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x83(h) xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x83(i) xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94,
xe2x80x83(j) xe2x80x94Oxe2x80x94,
xe2x80x83(k) xe2x80x94S(O)nxe2x80x94, wherein n is 0, 1 or 2,
xe2x80x83(l) xe2x80x94C(O)xe2x80x94Oxe2x80x94,
xe2x80x83(m) xe2x80x94Oxe2x80x94C(O)xe2x80x94,
xe2x80x83(n) xe2x80x94C(O)xe2x80x94; and
and R9 is selected from the group consisting of:
(a) alkyl optionally substituted with a substituent selected from the group consisting of
(aa) aryl,
(bb) substituted aryl,
(cc) heteroaryl, and
(dd) substituted heteroaryl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl,
(e) substituted heteroaryl, and
(f) heterocycloalkyl,
D. R is selected from the group consisting of
(1) hydrogen;
(2) methyl substituted with a moiety selected from the group consisting of
(a) CN,
(b) F,
(c) xe2x80x94CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl,
(d) xe2x80x94S(O)n R10xe2x80x94, wherein n is 0, 1 or 2 and R10 is as previously defined,
(e) xe2x80x94NHxe2x80x94C(O) R10, wherein R10 is as previously defined,
(f) xe2x80x94NHxe2x80x94C(O)N R11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl;
(3) alkyl;
(4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) C1-C3-alkoxy,
(d) C1-C3-alkoxy-C1-C3-alkoxy,
(e) oxo,
(f) Oxe2x80x94SO2-(substituted C1-C6-alkyl),
(g) xe2x80x94N3,
(h) xe2x80x94CHO,
(i) xe2x80x94NR13R14 wherein R13 and R14 are selected from the group consisting of
(i) hydrogen,
(ii) C1-C12-alkyl,
(iii) substituted C1-C12-alkyl,
(iv) C2-C12-alkenyl,
(v) substituted C2-C12-alkenyl,
(vi) C2-C12-alkynyl,
(vii) substituted C2-C12-alkynyl,
(viii) aryl,
(ix) C3-C8-cycloalkyl,
(x) substituted C3-C8-cycloalkyl,
(xi) substituted aryl,
(xii) heterocycloalkyl,
(xiii) substituted heterocycloalkyl,
(xiv) C1-C12-alkyl substituted with aryl,
(xv) C1-C12-alkyl substituted with substituted aryl,
(xvi) C1-C12-alkyl substituted with heterocycloaryl,
(xvii) C1-C12-alkyl substituted with substituted heterocycloaryl,
(xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
(xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C1-C12-alkyl substituted with heteroaryl, and
(xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
or R13 and R14 are taken together with the atom to which they are attached form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
(i) halogen,
(ii) hydroxy,
(iii) C1-C3-alkoxy,
(iv) C1-C3-alkoxy-C1-C3-alkoxy,
(v) oxo,
(vi) C1-C3-alkyl,
(vii) halo-C1-C3-alkyl, and
(viii) C1-C3-alkoxy-C1-C3-alkyl;
(j) xe2x80x94CO2R10 wherein R10 is as previously defined,
(k) xe2x80x94C(O)R11R12 wherein R11 and R12 are as previously defined,
(l) xe2x95x90Nxe2x80x94Oxe2x80x94R10 wherein R10 is as previously defined,
(m) xe2x80x94CN,
(n) xe2x80x94Oxe2x80x94S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously defined,
(o) aryl,
(p) substituted aryl,
(q) heteroaryl,
(r) substituted heteroaryl,
(s) C3-C8-cycloalkyl,
(t) substituted C3-C8-cycloalkyl,
(u) C1-C12-alkyl substituted with heteroaryl,
(v) heterocycloalkyl,
(w) substituted heterocycloalkyl,
(x) xe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined,
(y) xe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R 2 are as previously defined,
(z) xe2x95x90Nxe2x80x94NR13R14 wherein R13 and R14 are as previously defined,
(aa) xe2x95x90Nxe2x80x94R9 wherein R9 is as previously defined,
(bb) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined, and
(cc) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined;
(5) C3-alkenyl substituted with a moiety selected from the group consisting of
(a) halogen,
(b) xe2x80x94CHO,
(c) xe2x80x94CO2R10 wherein R10 is as previously defined,
(d) xe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(e) xe2x80x94C(O)R9 wherein R9 is as previously defined,
(f) xe2x80x94CN,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl,
(j) substituted heteroaryl,
(k) C3-C8-cycloalkyl, and
(l) C1-C12-alkyl substituted with heteroaryl;
(6) C4-C10-alkenyl;
(7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) C1-C3-alkoxy,
(c) oxo,
(d) xe2x80x94CHO,
(e) xe2x80x94CO2R10 wherein R10 is as previously defined,
(f) xe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(g) NR13R14 wherein R13 and R14 are as previously defined,
(h) xe2x95x90Nxe2x80x94Oxe2x80x94R10 wherein R10 is as previously defined,
(i) xe2x80x94CN,
(j) xe2x80x94Oxe2x80x94S(O)nR10 wherein n is 0, 1 or 2 and R10 is as previously defined,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) C3-C8-cycloalkyl,
(p) C1-C12-alkyl substituted with substituted heteroaryl,
(q) xe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined,
(r) xe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined,
(s) xe2x95x90Nxe2x80x94NR13R14 wherein R13 and R14 are as previously defined,
(t) xe2x95x90Nxe2x80x94R9 wherein R9 is as previously defined,
(u) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)R10 wherein R10 is as previously defined, and
(v) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)NR11R12 wherein R11 and R12 are as previously defined;
(8) C3-C10-alkynyl;
(9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
(a) trialkylsilyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl, and
(e) substituted heteroaryl; and
(10) C(O)NR7R8 where R7 and R8 are previously defined;
E. Ra is selected from a group consisting of
(1) hydrogen;
(2) C1 alkyl further substituted with a one or more substituents selected from a group consisting of
(a) hydroxyl,
(b) halogen,
(c) thiol, which can be further subsituted with and alkyl or subsituted alkyl group
(d) C1-C12-alkyl which can be further substituted by halogen, hydroxyl alkoxy, or amino,
(e) C1-C3-alkoxy,
(f) C1-C3-thioalkoxy,
(g) amino,
(h) alkylamino,
(i) dialkylamino,
(j) nitrile,
(k) nitro,
(l) amido,
(m) carboxylic acid,
(n) ester,
(o) azido,
(p) xe2x95x90Nxe2x80x94Oxe2x80x94R10, wherein R10 is as previously defined,
(q) xe2x95x90Nxe2x80x94R9, wherein R9 is as previously defined,
(r) xe2x95x90Nxe2x80x94NR13R14, wherein R13 and R14 are as previously defined,
(s) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)R10, wherein R10 is as previously defined, and
(t) xe2x95x90Nxe2x80x94NHxe2x80x94C(O)NR11R12, wherein R11 and R12 are as previously defined;
(3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
(4) -C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
(5) aryl, which can be further substituted with C1-C12-alkyl, and one or more halo groups;
(6) CHO;
(7) xe2x80x94CO2H;
(8) xe2x80x94CN;
(9) xe2x80x94CO2R10, wherein R10 is as previously defined;
(10) xe2x80x94C(O)NR11R12, wherein R11 and R12 are as previously defined;
(11) xe2x80x94C(O)R9 wherein R9 is as previously defined; and
(12) thioester;
with the proviso that in formula II, when Z is amino or substituted amino, then Ra can not be xe2x80x94CH2OH, xe2x80x94NR4R6, or xe2x80x94(CH2)n NR4R6, wherein R4 and R6 are selected from the group consisting of hydrogen, loweralkyl and aralkyl;
F. Rb is hydrogen, halogen or C1-C12-alkyl which can be further substituted by one or more halo groups, or Rb can be taken together with V to form a double bond;
G. Rc is hydrogen or a hydroxy protecting group;
H. Rd is selected from the group consisting of
(1) C1-C12-alkyl,
(2) C1-C12-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy, and
(c) C1-C3-alkoxy,
(3) C3-C7-cycloalkyl,
(4) C2-C4-alkenyl, and
(5) C2-C4-alkynyl;
I. Re is hydroxyl, amino, or alkylamino; or Re and Ra may be taken together to form an epoxide, a carbonyl, an olefin, or a subsituted olefin; or Re and Ra when taken together with the atom to which they are attached form a spiro ring consisting of C3-C7-carbocyclic, carbonate or carbamate wherein the nitrogen atom can be unsubstituted or substituted with an alkyl group; or Re and T when taken together with the carbon atoms to which they are attached form a ring of the structure 
xe2x80x83wherein L is methylene or carbonyl and P is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NR1xe2x80x94 wherein R1 is as previously defined; provided that when L is methylene, T is xe2x80x94Oxe2x80x94 and P is xe2x80x94Oxe2x80x94;
J. Rg is hydrogen, R where R is as previously defined; or Rg may be taken together with Y, seperated by a linker of the formula xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94, to form a cyclic moiety;
K. Rh is selected from the group consisting of
(1) hydrogen,
(2) xe2x80x94ORj, where Rj is hydrogen or a hydroxy protecting group,
(3) halogen,
(4) OC(O)NHRi wherein Ri is selected from a group consisting of
(a) C1-C4 alkyl,
(b) C1-C4 aminoalkyl where the amino group is substituted with one or two groups selected from
(i) C1-C4 alkyl,
(ii) C1-C4 alkyl substituted with halogen,
(iii) C1-C4 alkyl substituted with alkoxy,
(iv) C1-C4 alkyl substituted with hydroxyl,
(v) C1-C4 alkyl substituted with aryl,
(vi) C1-C4 alkyl substituted with substituted aryl,
(vii) C1-C4 alkyl substituted with heteroaryl,
(viii) C1-C4 alkyl substituted with substituted heteroaryl,
(ix) C3-C6 cycloalkyl; and
L. A, B, D, and E are independently selected from the group consisting of:
(1) hydrogen;
(2) C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of:
(a) aryl,
(b) substituted aryl,
(c) heteroaryl,
(d) substituted heteroaryl,
(e) heterocycloalkyl,
(f) hydroxy,
(g) C1-C6-alkoxy,
(h) halogen selected from the group consisting of Br, Cl, F or I, and
(i) NR7R8 where R7 and R8 are as previously defined;
(3) C3-C7-cycloalkyl;
(4) aryl;
(5) substituted aryl;
(6) heteroaryl;
(7) substituted heteroaryl;
(8) heterocycloalkyl; and
(9) a group selected from option (2) above further substituted with xe2x80x94Mxe2x80x94R9, wherein M and R9 are as previously defined; or
any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(C1-C6-alkyl-)-, xe2x80x94N(aryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-aryl-C1-C6-alkyl-)-, xe2x80x94N(heteroaryl-C1-C6-alkyl-)-, xe2x80x94N(substituted-heteroaryl-C1-C6-alkyl-)-, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)nxe2x80x94, wherein n is 1 or 2, xe2x80x94C(O)xe2x80x94NH, xe2x80x94C(O)xe2x80x94NR12, wherein R12 is as previously defined, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94NR12xe2x80x94C(O)xe2x80x94, wherein R12 is as previously defined, and xe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94; with the provision that at least two of A, B, D, and E are hydrogen.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (III): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rc, Rd, Re, Rg and Rh have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (IV): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rb, Rc, Rd, Re, and Rg have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (v): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, Y, Z, R, Ra, Re, Rd, and Rh have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (VI): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rb, Rc, and Rd have the meanings defined above. In another embodiment, illustrative compounds of formula (VI) have the structure of formula (VIa): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein W, Rf, R, Ra, Rc, and Rd have the meanings defined above. Illustrative, but nonlimiting examples include, without limitation, compounds of formula (VIa(1)): 
wherein R is H, ethyl or vinyl, and Rxe2x80x2 is H or F;
compounds of formula (VIa(2)): 
wherein R is H, ethyl or vinyl, Rxe2x80x2 is H or F, and Y is H, halogen, amino, C1-C4 alkyl, hydroxy, alkoxy, alkylamino, cyano or substituted C1-C4 alkyl;
compounds of formula (VIa(3)): 
wherein R is H, CF3, ethyl or vinyl, and Rxe2x80x2 is H or F;
compounds of formula (VIa(4)): 
wherein R is H, CF3, ethyl or vinyl, and Rxe2x80x2 is H or F; and
compounds of formula (VIa(5)): 
wherein R is H, CF3, ethyl or vinyl, and Rxe2x80x2 is H or F.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (VII): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, D, E, R, Ra, Rb, Rc, and Rd have the meanings defined above.
In another embodiment, the present invention provides compounds of formula (II) above having the structure of the following formula (VIII): 
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rc, and Rd have the meanings defined above.
In certain aspects, representative compounds of formulas II, III, IV, V, VI, VII, or hydrogen, substituted or unsubstituted C1-C12-alkyl, C2-C4-alkenyl, xe2x80x94C2-C4-alkynyl, aryl or thioester; X is xe2x95x90O; L is CO; P is xe2x95x90O; T is NH or N(Wxe2x80x94Rf) wherein W is as previously defined and Rf is an alkyl or subsituted alkyl group, which may be further subsituted by a heteroaryl selected from but not limited to 
A, B, D, and E are H; and R is methyl, allyl, propyl, xe2x80x94CH2CHO, xe2x80x94CH2CHxe2x95x90NOH, xe2x80x94CH2CHxe2x95x90NOH, xe2x80x94CH2CN, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2NHCH2-phenyl, xe2x80x94CH2CH2-NHCH2CH2-phenyl, xe2x80x94CH2CH2xe2x80x94NHCHxe2x80x94(CO2CH3)CH2-phenyl, xe2x80x94CH2CH2NHCH2-(4-pyridyl), xe2x80x94CH2CH2NHCH2-(4-quinolyl), xe2x80x94CH2CHxe2x95x90CH-phenyl, xe2x80x94CH2CH2CH2phenyl, xe2x80x94CH2CHxe2x95x90CH-(4-methoxyphenyl), xe2x80x94CH2CHxe2x95x90CH-(4-chlorophenyl), xe2x80x94CH2CHxe2x95x90CH-(3-quinolyl), xe2x80x94CH2CH2CH2OH, xe2x80x94CH2C(O)OH, xe2x80x94CH2CH2 HCH3, xe2x80x94CH2CH2NHCH2OH, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2CH2(1-morpholinyl), xe2x80x94CH2C(O)NH2, xe2x80x94CH2NHC(O)NH2, xe2x80x94CH2NHC(O)CH3, xe2x80x94CH2F, xe2x80x94CH2CH2OCH3, xe2x80x94CH2CH3, xe2x80x94CH2CHxe2x95x90CH(CH3)2, xe2x80x94CH2CH2CH(CH3)CH3, xe2x80x94CH2CH2OCH2CH2OCH3, xe2x80x94CH2SCH3, -cyclopropyl, xe2x80x94CH2OCH3, xe2x80x94CH2CH2F, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2CH2CHO, xe2x80x94C(O)CH2CH2CH3, xe2x80x94CH2-(4-nitrophenyl), xe2x80x94CH2-(4-chlorophenyl), xe2x80x94CH2-(4-methoxyphenyl), xe2x80x94CH2-(4-cyanophenyl), xe2x80x94CH2CHxe2x95x90CHC(O)OCH3, xe2x80x94CH2CHxe2x95x90CHC(O)OCH2CH3, xe2x80x94CH2CHxe2x95x90CHCH3, xe2x80x94CH2CHxe2x95x90CHCH2CH3, xe2x80x94CH2CHxe2x95x90CHCH2CH2CH3, xe2x80x94CH2CHxe2x95x90CHSO2-phenyl, xe2x80x94CH2Cxe2x89xa1Cxe2x80x94Si(CH3)3, xe2x80x94CH2Cxe2x89xa1CCH2CH2xe2x80x94CH2CH2CH3, xe2x80x94CH2 Cxe2x89xa1CCH3, xe2x80x94CH2-(2-pyridyl), xe2x80x94CH2-(3-pyridyl), xe2x80x94CH2-(4-pyridyl), xe2x80x94CH2-(4-quinolyl), xe2x80x94CH2NO2, xe2x80x94CH2C(O)OCH3, xe2x80x94CH2C(O)-phenyl, xe2x80x94CH2C(O)CH2CH3, xe2x80x94CH2Cl, xe2x80x94CH2S(O)2-phenyl, xe2x80x94CH2CHxe2x95x90xe2x95x90CHBr, xe2x80x94CH2 CHxe2x95x90CH-(4-quinolyl), xe2x80x94CH2 CH2 CH2-(4-quinolyl), xe2x80x94CH2 CHxe2x95x90CH-(5-quinolyl), xe2x80x94CH2CH2CH2-(5-quinolyl), xe2x80x94CH2CHxe2x95x90CH-(4-benzoxazolyl), xe2x80x94CH2CHxe2x95x90CH-(7-benzimidazolyl), xe2x80x94CH2-(3-iodophenyl), xe2x80x94CH2-(2-naphthyl), xe2x80x94CH2xe2x80x94CHxe2x95x90CH-(4-fluorophenyl), xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CN, xe2x80x94CH2CHxe2x95x90CH-(quinoxalin-6-yl), xe2x80x94CH2CHxe2x95x90CH-([1,8]-naphthyridin-3-yl), xe2x80x94CH2CHxe2x95x90CH-([1,5]-naphthyridin-3-yl), xe2x80x94CH2CHxe2x95x90CH-(5-pyridin-2-yl-thiophen-2-yl), xe2x80x94CH2CHxe2x95x90CH-(5-pyridin-3-yl-thiophen-2-yl), xe2x80x94CH2CHxe2x95x90CH-(5-(6-methylpyridin-3-yl)-thiophen-2-yl), xe2x80x94CH2CHxe2x95x90CH-(5-thiazol-2-yl-thiophen-2-yl), xe2x80x94CH2CHxe2x95x90CH-(5-thiazol-5-yl-thiophen-2-yl), xe2x80x94CH2CHxe2x95x90CH-(5-pyrimidin-2-yl-thiophen-2-yl), xe2x80x94CH2CHxe2x95x90CH-(5-pyrazin-2-yl-thiophen-2-yl), xe2x80x94CH2Cxe2x89xa1C-(quinolin-3-yl), xe2x80x94CH2Cxe2x89xa1C-(quinoxalin-6-yl), xe2x80x94CH2Cxe2x89xa1C-([1,8]-naphthyridin-3-yl), xe2x80x94CH2Cxe2x89xa1C-([1,5]-naphthyridin-3-yl), xe2x80x94CH2Cxe2x89xa1C-(5-pyridin-2-yl-thiophen-2yl), xe2x80x94CH2Cxe2x89xa1C-(5-pyridin-3-yl-thiophen-2-yl), xe2x80x94CH2Cxe2x89xa1C-(5-(6-methylpyridin-3-yl)-thiophen-2-yl), xe2x80x94CH2Cxe2x89xa1C-(5-thiazol-2-yl-thiophen-2-yl), xe2x80x94CH2Cxe2x89xa1C-(5-thiazol-5-yl-thiophen-2-yl), xe2x80x94CH2Cxe2x89xa1C-(5-pyrimidin-2-yl-thiophen-2-yl), or xe2x80x94CH2Cxe2x89xa1C-(5-pyrazin-2-yl-thiophen-2-yl).
Definitions
As used throughout this specification and the appended claims, the following terms have the meanings specified.
The term xe2x80x9calkylxe2x80x9d refers to saturated, straight- or branched-chain hydrocarbon groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: xe2x80x94CH(CH3)2, xe2x80x94CH(CH3)(CH2CH3), xe2x80x94CH(CH2CH3)2, xe2x80x94C(CH3)3, xe2x80x94C(CH2CH3)3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CH(CH3)(CH2CH3), xe2x80x94CH2CH(CH2CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2C(CH2CH3)3, xe2x80x94CH(CH3)CH(CH3)(CH2CH3), xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CH2CH(CH3)(CH2CH3), xe2x80x94CH2CH2CH(CH2CH3)2, xe2x80x94CH2CH2C(CH3)3, xe2x80x94CH2CH2C(CH2CH3)3, xe2x80x94CH(CH3)CH2CH(CH3)2, xe2x80x94CH(CH3)CH(CH3)CH(CH3)2, xe2x80x94CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. Alkyl also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus the phrase alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 12 carbon atoms.
The phrase xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heterocyclyl group, or cycloalkyl group. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. Another preferred substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Still other preferred substituted alkyl groups include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
The terms xe2x80x9cC1-C3-alkylxe2x80x9d, xe2x80x9cC1-C6-alkylxe2x80x9d, and xe2x80x9cC1-C12-alkylxe2x80x9d as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom. Examples of C1-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl, examples of C1-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl. Examples of C1-C12-alkyl radicals include, but are not limited to, all the foregoing examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl.
The term xe2x80x9cC1-C6-alkoxyxe2x80x9d as used herein refers to a C1-C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term xe2x80x9cC2-C12-alkenylxe2x80x9d denotes a monovalent group derived from a hydrocarbon moiety containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The term xe2x80x9cC2-C12-alkynylxe2x80x9d as used herein refers to a monovalent group derived from a hydrocarbon moiety containing from two to twelve carbon atoms and having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Representative alkynyl groups include ethynyl, propynyl and the like.
The term 14-member macrolide antibiotics used herein include the natural products erythromycin, narbomycin, lakamycin, and oleandomycin, as well as derivatives such as roxithromycin, clarithromycin, dirithromycin, flurithromycin, and the ketolides (telithromycin, HMR 3004, TE-802, TE-810, ABT 773).
The term xe2x80x9calkylenexe2x80x9d denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
The term xe2x80x9cC1-C3-alkylaminoxe2x80x9d as used herein refers to one or two C1-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of C1-C3-alkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
The term xe2x80x9coxoxe2x80x9d denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i.e. a carbonyl group).
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9cC3-C12-cycloalkylxe2x80x9d denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term xe2x80x9calkylaminoxe2x80x9d refers to a group having the structure xe2x80x94NHRxe2x80x2 wherein Rxe2x80x2 is alkyl, as previously defined. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino.
The term xe2x80x9cdialkylaminoxe2x80x9d refers to a group having the structure xe2x80x94NRxe2x80x2Rxe2x80x3 wherein Rxe2x80x2 and Rxe2x80x3 are independently selected from alkyl, as previously defined. Additionally, Rxe2x80x2 and Rxe2x80x3 taken together may optionally be xe2x80x94(CH2)kxe2x80x94 where k is an integer of from 2 to 6. Examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, methylpropylamino, and piperidino.
The term xe2x80x9chaloalkylxe2x80x9d denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d represents an ester group; i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like.
The term xe2x80x9cthioalkoxyxe2x80x9d refers to an alkyl group as previously defined attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein refers to a group of formula xe2x80x94CHO.
The term xe2x80x9ccarboxyxe2x80x9d as used herein refers to a group of formula xe2x80x94CO2H.
The term xe2x80x9ccarboxamidexe2x80x9d as used herein refers to a group of formula xe2x80x94CONHRxe2x80x2Rxe2x80x3 wherein Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl, or Rxe2x80x2 and Rxe2x80x3 taken together may optionally be xe2x80x94(CH2)kxe2x80x94 where k is an integer of from 2 to 6.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring of which one atom of the cyclic or bicyclic ring is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and naphthyridinyl. Representative examples of heteroaryl moieties include, but not limited to, pyridin-3-yl-1H-imidazol-1-yl, phenyl-1H-imidazol-1-yl, 3H-imidazo[4,5-b]pyridin-3-yl, quinolin-4-yl, 4-pyridin-3-yl-1H-imidazol-1-yl, quinolin-4-yl, quinolin-2-yl, 2-methyl-4-pyridin-3-yl-1H-imidazol-1-yl, 5-methyl-4-pyridin-3-yl-1H-imidazol-1-yl, 1H-imidazo[4,5-b]pyridin-1-yl, pyridin-3-ylmethyl, 3H-imidazo[4,5-b]pyridin-3-yl, 4-pyrimidin-5-yl-1H-imidazol-1-yl, 4-pyrazin-2-yl-1H-imidazol-1-yl, 4-pyridin-3-yl-1H-imidazol-1-yl, 4-pyridin-4-yl-1H-imidazol-1-yl, 4-(6-methylpyrid-3-yl)-1H-imidazol-1-yl, 4-(6-fluoropyridin-3-yl)-1H-imidazol-1-yl, 5-(3-aminophenyl)-1,3-thiazol-2-yl, 3-pyridin-3-ylphenoxy, 4-pyridin-3-ylphenoxy, 3H-imidazo[4,5-b]pyridin-3-yl, 4-phenyl-1H-imidazol-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, quinolin-3-yl, 2-methylquinolin-4-yl, trifluoromethyl)quinolin-4-yl, 8-(trifluoromethyl)quinolin-4-yl, 2-phenoxyethoxy, 4-pyridin-3-ylphenoxy, 3-pyridin-3-ylphenoxy, 5-phenyl-1,3-thiazole, 5-(2,4-difluorophenyl)-1,3-thiazol-2-yl, 5-(3-aminophenyl)-1,3-thiazol-2-yl, (3,3xe2x80x2-bipyridin-5-ylmethyl)(methyl)amino, (6-methylpyridin-3-yl)-1H-imidazol-1-yl, methyl(quinolin-3-ylmethyl)amino, 3-phenylisoxazol-5-yl, 3-(4-methylphenyl)isoxazol-5-yl and the like.
The term xe2x80x9cheterocycloalkylxe2x80x9d as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term xe2x80x9cheteroarylalkylxe2x80x9d as used herein, refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group wherein the alkylene group is of one to four carbon atoms.
xe2x80x9cHydroxy-protecting groupxe2x80x9d, as used herein, refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf., for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991). Examples of hydroxy-protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl benzoyl, and the like.
The term xe2x80x9cketone protecting groupxe2x80x9d, as used herein, refers to an easily removable group which is known in the art to protect a ketone group against undesirable reaction during synthetic procedures and to be selectively removable. The use of ketone-protecting groups is well known in the art for protecting groups against undesirable reaction during a synthetic procedure and many such protecting groups are known, cf., for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991). Examples of ketone-protecting groups include, but are not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.
The term xe2x80x9cprotected-hydroxyxe2x80x9d refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
The term xe2x80x9csubstituted arylxe2x80x9d as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9csubstituted heteroarylxe2x80x9d as used herein refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9csubstituted heterocycloalkylxe2x80x9d as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Synthetic Methods
Synthesis of the compounds of the invention can be broadly summarized as follows. 1) The free alcohols on the sugars and the reduced C9 ketone are protected in a fashion that allows for the relatively efficient elimination of the C12 hydroxy group (i.e., without burdensome competing side products) to form an alkene intermediate. 2) The alkene intermediate is converted to an epoxide, diol, or ketone intermediate. 3) The epoxide, diol, and ketone is then used to introduce new C12 substituents. 4) Further manipulations are then carried out as needed to generate the desired final products.
1. Useful Intermediates for Producing Useful C12 Olefins
The above-described disclosure of the Lartey patent (U.S. Pat. No. 5,217,960) is limited, because the C9 amine disclosed therein cannot be converted to a ketone to access C9-keto analogs combined with C12 modifications. The unavailability of this option is unfortunate in view of the fact that compounds lacking the C9-keto group generally show weak antibacterial activity. Alternatively the disclosure of the Hauske patent (U.S. Pat. No. 4,857,641) typically leads to a complex mixture of products. Thus, Hauske does not show or suggest synthetically reasonable routes to address the deficiencies of Lartey.
Thus, in one aspect, the invention provides macrolide and ketolide synthesis procedures having advantages over the prior teachings of Hauske and Lartey.
Surprisingly, the inventors have found that the C9 and C11-diols, when protected as acid labile acetonides or base labile carbonates, provide relatively efficient elimination at C12 over C6. Moreover, the inventors have discovered that the elimination reaction to form the C12 alkene can be more efficiently carried out when acetates are not used to protect the 2xe2x80x2 and 4xe2x80x3 positions of the associated sugars as is taught by the prior art. Representative protecting groups used in the novel and surprisingly effective synthesis methodologies provided by the present invention include, but are not limited to, benzyl esters and TMS ethers. This invention also provides still other alternative protecting groups that lead to useful C12 alkene intermediates. For example, the five illustrative compounds below have been found to be useful precursors for the elimination reaction to form the corresponding C12 alkenes. 
2. New Macrolide and Ketolide Antibiotics Arising from an Epoxide Intermediate
In one aspect, this invention provides means for functionalizing the macrolide C12 methyl group with optionally substituted alkyl, alkenyl, alkynyl, and aryl groups to give a new, monosubstituted C12 methyl group. It has been found that the alkyl and aryl cuprates LiMe2Cu and LiPh2Cu can be efficiently added to a C12 epoxide to produce, effectively, the respective ethyl and benzyl substituents at C12. This invention also contemplates a number of novel substituents at C12 that may be similarly introduced via the reagents shown below: 
R2CuLi where R=perfluoroalkyl, Fxe2x80x94, CNxe2x80x94, CNCH2xe2x80x94, CNCHRxe2x80x94
In addition to the above carbanion equivalents, nucleophiles (such as azides and thiolates) known to react with epoxides are also included with the methods and compounds provided by the invention.
3. New C12 Ketone Intermediate
In other aspects, the present invention relates to methods for introducing a ketone at the C12 position. In this aspect, a C12 olefin can undergo ozonolysis to form the corresponding ketone. This procedure can be efficiently carried out if the amino group on the desosamine sugar is preferably protonated to minimize generating unwanted side products. This invention also contemplates other methods for producing a ketone at C12 such as treatment of the alkene with RuO4 or dihydoxylating the precursor olefin followed by diol cleavage with NaIO4.
4. Method for Generating New Macrolides and Ketolides from Ketone Intermediate.
A. Addition of Nucleophiles from Top Face
Unlike the epoxide route that only allows access to monosubstituted C12 methyl groups, this procedure further relates to methods for replacing the C12 methyl group entirely with substituents such as H or CF3, such as shown in Scheme A, below. 
B. Introduction of a Tertiary Amine at C12
The C12 ketone moiety is useful in the synthesis of derivatives with a C12 amine. The following xe2x80x9creverse carbamatexe2x80x9d analog containing a 4xe2x80x3 benzoate has been synthesized. 
5. Representative Examples of Other C12 modified Compounds
Further examples of analogs that may be synthesized using the above methods are described in the following section. 
Scheme 1a illustrates one embodiment of the invention, whereby novel C12 modifications may be introduced via an epoxide intermediate. Starting with compound 1, the free hydroxyl groups on the sugar moieties may be protected as benzyl esters followed by stereoselective reduction of the C9 ketone to give compound 2. After protecting the two remaining secondary alcohols as their formate esters, the C12 tertiary alcohol 3 may be treated with thionyl chloride and an amine base to form the exocyclic alkene 4. The formate protecting groups may then be removed by treatment with MeOH. These conditions may also result in deprotection of the benzyl esters, which can be overcome by an additional protection step to reinstall the benzyl protecting groups, if necessary. Olefin 5 may then be epoxidized and the resulting C9 alcohol 6 selectively reoxidized back to the ketone 7. Ring opening of epoxide 7 with a nucleophile to give 8 followed by global removal of the sugar protecting groups furnishes analog 9 with a new C21 substituent. 
A similar reaction sequence shown in Scheme 1b has also been carried out where an acetonide, rather than formate, is used to protect the C9-C11 diol of 2 to give compound 10. Treatment of alcohol 10 with SOCl2Et3N gives the C12 olefin 11 that is then epoxidized. The epoxide ring opening may be successfully carried out with LiMe2CuandLiPh2Cu. The resulting intermediates are useful for accessing C12 telithromycin analogs and demonstrate the viability of cuprate mediated C12 epoxide openings. 
In another embodiment of the invention, the C12 modification can be introduced via a ketone intermediate. In this embodiment, olefin 11 is converted to ketone 12 under ozonolytic conditions, as shown in Scheme 2a, above. H or CF3 can be added to the ketone product. The resulting C12 alcohol of 13 may be inverted via a four-step process involving the initial steps of activating the alcohol to give 14 and then removing the acetonide. Here, two options are possible. The sugar moiety at C3 may also be removed during the acetonide deprotection if 10% HCl/MeCN or PPTS (EtOH, 90xc2x0 C.) is used; use of HOAc/H2O/MeOH removes only the acetonide (Scheme 2b). The C3 and C9 alcohols of 15 are regioselectively oxidized to 16 and the inversion step is next effected under basic conditions to give 17. During this process, a C10-C11 alkene also forms that can be refunctionalized by an intramolecular michael addition as taught in U.S. Pat. No. 5,635,485. More specifically, an activated carbamate at C12 of 18, formed by condensation of the alcohol 17 with carbonyl diimidazole may be coupled to a variety of alkyl amines. The resulting intermediate then cyclizes in situ to form the cyclic carbamate 19. Removal of the remaining protecting groups yields the novel ketolides 20. A similar route as utilized for the C12-hydrogen series, is outline in Scheme 3 for the C12-trifluoromethyl series. 
These manipulations may also be carried out on erythromycin as shown in Scheme 4 above. These transformations parallel those shown in the above example (Scheme 1, epoxide route) but are applied to a more demanding case wherein the intermediates contain a free C6 tertiary alcohol. Acetonide and carbonate protecting groups are useful in directing olefin formation at C12 over C6. Representative sugar protecting groups for this purpose include, for example, TMS and benzyl esters. 
With alkene 30 successfully in hand, epoxidation or ozonolysis can lead to useful intermediates for generating novel compounds containing a modified C12 substituent. Scheme 5a shows the process to prepare C12-derivatives by way of C12,21-epoxide. Scheme 5b outlines modifications of C12-ketone. 
Greater diversity at C12 can also be attained by conversion of the C12 ketone to an imine prior to the introduction of nucleophiles as shown in Scheme 6. 
Dihydroxylation of alkene 30 can lead to useful intermediates for generating novel compounds containing modified C12 substituents as depicted in Scheme 7. Upon deprotection of the C9-C12 acetonide the C12 exocyclic olefin can be dihydroxylated yielding a tetraol that can be selectively protected at the primary C21 alcohol as the acetate. Selective oxidation of the C9 hydroxyl and mesylation of the C11 hydroxyl followed by elimination yields the C9-C11 enone. Removal of the cladinose and acetate yields a triol that can be bis oxidized to give a C12 formyl substituent. A Wittig reaction coverts this to the C12 vinyl substituent and then following in the manner described already the cyclic carbamate is installed. 
Further modification of dihydroxylated derived compound A can lead to further C12 modified macrolides, as described in Scheme 8. Selective silyl protection of the primary alcohol in A, followed by C3 oxidation, conversion to the cyclic carbamate in the usual fashion and disilylation yields the C12 hydroxymethyl macrolide. The C21 hydroxyl can be sulfonylated to form the C21 mesylate as depicted. The C12 hydroxymethyl can also be oxidized to form the C12 formyl macrolide. Wittig reaction on the C12 formyl, or reaction with organometallics, followed by oxidation yields the C12 alkenyl and C12 acteyl macrolides respectively as depicted.
Scheme 9 outlines the synthetic method to make novel C12 anhydrolides 308. Route 1 shows that novel C12 enone-ol 305 can be converted to 11,12-cyclic carbamate 306 in a similar manner as shown in Schene 2b. Further modifications include removal of cladinose under acidic condition, activating 3-hydroxy as mesylate and elimination under basic condition to give desired anhydrolide 308. Alternatively, C2, C3 double bond can be formed prior to the formation of C11, C12-cyclic carbamate as shown in Route 2. 
Scheme 10 depicts representative methods used construct side chains incorporated into the macrolides of the invention.
In the foregoing reaction schemes and other synthesis methods disclosed herein, diol protecting groups for the C9-C11 diol, wherein both alcohols are linked to form a 6-8 membered ring, may include, but are not limited to, those described in Greene and Wuts (1991), supra. Exemplary groups include cyclic acetals, such as methylene, ethylidene, 2,2,2-trichloroethylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimthoxybenzylidene, 2-nitrobenzylidene; ketals such as 1-t-butylethylidene, 1-phenylethylidene, and (4-methoxyphenyl)ethylidene, acetonide, cyclopentylidene, cyclohexylidene, and cylcoheptylidene; cyclic ortho esters such as methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, xcex1-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene, xcex1-(N,N-dimethylamino)benzylidene, 2-oxacyclopentylidene; cyclic silyl ethers such as di-t-buylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), tetra-t-butoxydisiloxane-1,2-diylidene; cyclic carbonates; and cyclic boronates such as ethyl, phenyl, their polymeric versions, and boronates linking two or more macrolides. Additionally, the diol as well as the sugar alcohols may be individually and independently protected with suitable alcohol blocking groups familiar to those skilled in the art. Exemplary protecting groups include but are not limited to silyl ethers such t-butyldimethyl-chlorosilyl, trimethylchlorosilyl, triisopropylchlorosilyl, triethylchlorosilyl, diphenylmethylsilyl, triphenylsilyl; optionally substituted ethers such as triphenylmethyl, methoxymethyl, methythiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, 1-ethoxyethyl ether, allyl, benzyl, p-methoxybenzyl, nitrobenzyl; aryl and alkyl esters such as benzoylformate, formate, acetate, trichloroacetate, trifluoracetate, pivaloate; and carbonates such as methyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl.
Pharmaceutical Compositions
Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer""s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or dry powder formulation for inhalation.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia. Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
Aerosolized formulations of the invention may be delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 xcexc. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds of the invention to the site of the infection. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
Aerosolization devices suitable for administration of aerosol formulations of the invention include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation of the invention into aerosol particle size predominantly in the size range from 1-5xcexc. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5xcexc range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb(trademark) and AeroDose(trademark) vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.), Sidestream(copyright) nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC(copyright) and Pari LC Star(copyright) jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Va.), and Aerosonic (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire(copyright) (Omron Healthcare, Inc., Vernon Hills, Ill.) ultrasonic nebulizers.
Compounds of the invention may also be formulated for use as topical powders and sprays that can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound(s) of this invention per day in single or multiple doses.
Abbreviations
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: AcOH for acetic acid; AIBN for azobisisobutyronitrile; Bu3SnH for tributyltin hydride; CDI for carbonyldiimidazole; DBU for. 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM for dichloromethane; DEAD for diethylazodicarboxylate; DMF for dimethylformamide; DMP for 2,2-dimethoxypropane DMSO for dimethylsulfoxide; DPPA for diphenylphosphoryl azide; Et3N for triethylamine; EtOAc for ethyl acetate; Et2O for diethyl ether; EtOH for ethanol; HOAc for acetic acid; LiHMDS or LiN(TMS)2 for lithium bis(trimethylsilyl)amide; MCPBA for meta-chloroperbenzoic acid; MeOH for methanol; MsCl for methanesulfonyl chloride; NaHMDS or NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NMO for N-methylmorpholine N-oxide; SOCl2 for thionyl chloride; PPTS for pyridium p-toluene sulfonate; Py for pyridine; TEA for triethylamine; THF for tetrahydrofuran; TMSCl for trimethylsilyl chloride; TMSCF3 for trimethyl(trifluoromethyl)-silane; TPP for triphenylphosphine; TPAP for tetra-n-propylammonium perruthenate; DMAP for 4-dimethylamino pyridine, TsOH for p-toluene sulfonic acid.
Referring to the examples that follow, compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module (Milford, Mass.). The analytical columns were Alltima C-18 reversed phase, 4.6xc3x97250 mm from Alltech (Deerfield, Ill.). A gradient elution was used, typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburg, Pa.). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1xc3x9750 mm; Solvent system: 5-95% (or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA; Flow rate 0.8 mL/min; Molecular weight range 500-1500; Cone Voltage 20 V; Column temperature 40 C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1xc3x9750 mm; Solvent system: 1-95% acetonitrile in water with 0.05% TFA; Flow rate 0.4 mL/min; Molecular weight range 150-850; Cone Voltage 50 V; Column temperature 30 C.). All masses are reported as those of the protonated parent ions.
GCMS analysis was performed on a Hewlett Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; Injector volume: 1 uL; Initial column temperature: 50 C.; Final column temperature: 250 C.; Ramp time: 20 minutes; Gas flow rate: 1 mL/min; Column: 5% Phenyl Methyl Siloxane, Model #HP 190915-443, Dimensions: 30.0 mxc3x9725 mxc3x970.25 m).
Nuclear magnetic resonance (NMR) analysis was performed with a Varian 300 Mhz NMR (Palo Alto, Calif.). The spectral reference was either TMS or the known chemical shift of the solvent. Some compound samples were run at elevated temperatures (i.e. 75xc2x0 C.) to promote increased sample solubility.
The purity of some of the invention compounds was assessed by elemental analysis (Desert Analytics, Tuscon, Ariz.)
Melting points were determined on a Laboratory Devices Mel-Temp apparatus (Holliston, Mass.).
Preparative separations were carried out using a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed phase column. Typical solvents employed for the Flash 40 Biotage system and flash column chromatography were dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl amine. Typical solvents employed for the reverse phase HPLC were varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
The foregoing may be better understood by reference to the following examples which are presented for illustration and not to limit the scope of the inventive concepts.